Triple-negative breast cancer (TNBC) is one of the most aggressive forms of human cancer, and currently has no targeted therapy. Chemotherapy is the only available treatment for TNBC patients, but is deleterious and not effective once tumor spreads. TNBC represents a major unmet medical need: about 20% of breast cancer incidences (240,000 women worldwide in 2012) are TNBC; TNBC disproportionally affects women of African and Hispanic descent, and younger women as early as in their 20s; and 80% of breast cancer in people with an inherited BRCA1 mutation is found to be TNBC. Breast cancer is a highly heterogeneous disease with five major subtypes: luminal A, luminal B, ErbB2, normal-like, and basal-like. Basal-like breast cancer is defined by markers characteristic of basal/myoepithelial cells, and by lack of expression of three receptors, i.e. estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (Her2/neu), hence commonly referred to as triple-negative breast cancer. As such, the available treatments for breast cancer targeting these receptors do not work for TNBC patients. TNBC distinguishes from other forms of breast cancer in tumor cell origination and progression. TNBC cells possess epithelial- mesenchymal transition characteristics including invasion, resistance to apoptosis, and cancer stem cell-like traits that permit tumor dissemination and growth at distant sites. Recently, we discovered key transcription factors that are constitutively activated and sustain over-expression of oncogenes, enabling rapid growth and spread (metastasis) of TNBC tumors. Our new small-molecule inhibitor, designed to block the transcription activities of these TNBC transcription factors, effectively blocks metastatic TNBC tumorigenesis in mice. To fully explore this unprecedented opportunity to develop safe and precision medicine against TNBC, we will accomplish two Specific Aims in the Phase I of this project, which are to develop highly potent and selective inhibitors that block triple-negative breast cancer tumorigenesis, and to simultaneously characterize our new epigenetic drug molecules as novel targeted therapeutic agents for TNBC. The Phase I results will prepare us for a more efficient Phase II study of an extensive pre-clinical evaluation of our most promising drug candidates in future human clinical trials.